This proposal describes a five-year training program, which will allow me to develop an independent academic career in clinical research using epidemiologic methods to study transmission and prevention of cytomegalovirus (CMV) in immunocompromised hosts. The initial focus will be on understanding the role of entry-specific neutralizing antibodies in different transplant settings, which will likely lead to the development of novel prevention strategies. CMV is a significant cause of morbidity and mortality after transplantation. Despite advances in early diagnosis and treatment, CMV infection remains associated with increased mortality and increased risk of bacterial and fungal infections, and with graft failure in solid organ transplantation (SOT). CMV transmission rates in SOT are much higher than in HCT, likely due to the concomitant transfer of humoral and cell-mediated immune cells that occurs with HCT. A novel CMV antigen (UL 131-128) that is essential for viral entry into epithelial and endothelial cells, and elicits neutralizing antibodies in natural infection has been discovered. Furthermore, a recent work in CMV vaccines demonstrates an inverse correlation between antibody levels and duration of viremia after primary infection. I propose two prospective and two retrospective studies to test the hypothesis that CMV infection and progression after transplantation is inversely related to the anti-UL131-128 neutralizing capacity. In the first aim, I will define the relationship between anti-UL131-128 neutralizing capacity and primary CMV infection after HCT in a prospective cohort, while controlling for the viral inoculum of the stem cell product and CMV-specific cellular immunity. In the second aim, I will examine the role of anti-UL131- 128 neutralizing antibodies, both endogenous and exogenous (via CMV hyperimmune globulin), in controlling progression of disease after HCT in two retrospective studies using archived samples. Finally, in the third aim, I will characterize the influence of ant-UL131-128 neutralizing antibodies in preventing late CMV disease following primary infection in liver transplantation. The proposed studies will advance our understanding of the clinical relevance of anti-UL131-128 neutralizing antibodies in the prevention of CMV transmission and progression to late disease, make significant contributions to the care of transplant patients, and provide a new tool for assessing risk of CMV acquisition in other important settings of primary infection such as congenital and neonatal infection. PROJECT NARRATIVE: Cytomegalovirus (CMV) is the most common viral infection after transplantation and causes significant morbidity and mortality in immunocompromised populations. A novel CMV antigen (UL 131-128) that is essential for viral entry, and elicits neutralizing antibodies in natural infection has been discovered. This proposal seeks define the role of these neutralizing antibodies in the prevention and control of primary CMV infection after transplantation, which will improve our care of transplant recipients and also provide critical knowledge about CMV immunobiology in other important settings of primary infection, such as congenital and neonatal infection.